tbuckley/cabot-search huggingface dataset:
Endothelial Loss of ETS1 Impairs Coronary Vascular Development and Leads to Ventricular Non-Compaction
Authors: Lu Wang, Lizhu Lin, Hui Qi, Ju Chen, Paul Grossfeld
Journal: Circulation Research (2022)

Rationale: Jacobsen syndrome is a rare chromosomal disorder caused by deletions in the long arm of human chromosome 11, resulting in multiple developmental defects including congenital heart defects. Combined studies in humans and genetically engineered mice implicate that loss of ETS1 (E26 transformation specific 1) is the cause of congenital heart defects in Jacobsen syndrome, but the underlying molecular and cellular mechanisms are unknown. Objective: To determine the role of ETS1 in heart development, specifically its roles in coronary endothelium and endocardium and the mechanisms by which loss of ETS1 causes coronary vascular defects and ventricular noncompaction. Methods and Results: ETS1 global and endothelial-specific knockout mice were used. Phenotypic assessments, RNA sequencing, and chromatin immunoprecipitation analysis were performed together with expression analysis, immunofluorescence and RNAscope in situ hybridization to uncover phenotypic and transcriptomic changes in response to loss of ETS1. Loss of ETS1 in endothelial cells causes ventricular noncompaction, reproducing the phenotype arising from global deletion of ETS1. Endothelial-specific deletion of ETS1 decreased the levels of Alk1 (activin receptor-like kinase 1), Cldn5 (claudin 5), Sox18 (SRY-box transcription factor 18), Robo4 (roundabout guidance receptor 4), Esm1 (endothelial cell specific molecule 1) and Kdr (kinase insert domain receptor), 6 important angiogenesis-relevant genes in endothelial cells, causing a coronary vasculature developmental defect in association with decreased compact zone cardiomyocyte proliferation. Downregulation of ALK1 expression in endocardium due to the loss of ETS1, along with the upregulation of TGF (transforming growth factor)-β1 and TGF-β3, occurred with increased TGFBR2/TGFBR1/SMAD2 signaling and increased extracellular matrix expression in the trabecular layer, in association with increased trabecular cardiomyocyte proliferation. Conclusions: These results demonstrate the importance of endothelial and endocardial ETS1 in cardiac development. Delineation of the gene regulatory network involving ETS1 in heart development will enhance our understanding of the molecular mechanisms underlying ventricular and coronary vascular developmental defects and will lead to improved approaches for the treatment of patients with congenital heart disease.
SARS-CoV-2 mRNA vaccination elicits robust antibody responses in children
Authors: Yannic C. Bartsch, Kerri J. St. Denis, Paulina Kaplonek, Jaewon Kang, Evan C. Lam, Madeleine D. Burns, Eva J. Farkas, Jameson P. Davis, Brittany P. Boribong, Andrea G. Edlow, Alessio Fasano, Wayne G. Shreffler, Dace Zavadska, Marina Johnson, David Goldblatt, Alejandro B. Balazs, Lael M Yonker, Galit Alter
Journal: Science Translational Medicine (2022)

Although children have been largely spared from coronavirus disease 2019 (COVID-19), the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) with increased transmissibility, combined with fluctuating mask mandates and school reopenings, has led to increased infections and disease among children. Thus, there is an urgent need to roll out COVID-19 vaccines to children of all ages. However, whether children respond equivalently to adults to mRNA vaccines and whether dosing will elicit optimal immunity remain unclear. Here, we aimed to deeply profile the vaccine-induced humoral immune response in 6- to 11-year-old children receiving either a pediatric (50 μg) or adult (100 μg) dose of the mRNA-1273 vaccine and to compare these responses to vaccinated adults, infected children, and children who experienced multisystem inflammatory syndrome in children (MIS-C). Children elicited an IgG-dominant vaccine-induced immune response, surpassing adults at a matched 100-μg dose but more variable immunity at a 50-μg dose. Irrespective of titer, children generated antibodies with enhanced Fc receptor binding capacity. Moreover, like adults, children generated cross-VOC humoral immunity, marked by a decline of omicron-specific receptor binding domain, but robustly preserved omicron spike protein binding. Fc receptor binding capabilities were also preserved in a dose-dependent manner. These data indicate that both the 50- and 100-μg doses of mRNA vaccination in children elicit robust cross-VOC antibody responses and that 100-μg doses in children result in highly preserved omicron-specific functional humoral immunity.
Low abundance members of the gut microbiome exhibit high immunogenicity
Authors: Geongoo Han, Hien Luong, Shipra Vaishnava
Journal: Gut Microbes (2022)

Studies identifying bacterial members that dictate host phenotype have focused mainly on the dominant members, and the role of low abundance microbes in determining host phenotypes and pathogenesis of diseases remains unexplored. In this study, we compared the gut bacterial community of mice with wide-ranging microbial exposure to determine if low abundance bacteria vary based on microbial exposure or remain consistent. We noted that similar to the high abundance bacterial community, a core community of low abundance bacteria made up a significant portion of the gut microbiome irrespective of microbial exposure. To determine the role of low abundance bacteria in regulating community composition and host gene expression, we devised a microbiome dilution strategy to "delete" out low abundance bacteria and engrafted the diluted microbiomes into germ-free mice. Our approach successfully excluded low abundance bacteria from small and large intestinal bacterial communities and induced global changes in microbial community composition in the large intestine. Gene expression analysis of intestinal tissue revealed that loss of low abundance bacteria resulted in a drastic reduction in expression of multiple genes involved MHCII antigen presentation pathway and T-cell cytokine production in the small intestine. The effect of low abundance bacteria on MHCII expression was found to be specific to the intestinal epithelium at an early timepoint post-colonization and correlated with bacteria belonging to the family Erysipelotrichaceae. We conclude that low abundance bacteria have a significantly higher immuno-stimulatory effect compared to dominant bacteria and are thus potent drivers of early immune education in the gut.
Authors’ reply to Reed
Authors: Haider J Warraich, Pankaj Kumar, Rishi K Wadhera
Journal: BMJ (2022)

<b>1364</b> <b>Objectives</b>: Increased serum alkaline phosphatase (SAP) in an asymptomatic patient may pose a diagnostic dilemma for the clinician. Major sources of SAP are bone and liver. A retrospective review was done to assess the value of routine bone scan (BS) to identify occult bone pathology such as Paget’s disease (PD) or metastatic disease as the source of elevated SAP. <b>Methods</b>: 87 BS were performed because of increased SAP (range 126-986 U/L, mean 222 U/L, reference range 25-125 U/L). There were 59 men and 28 women, age 29-87 years (mean 64 years). Patients with elevated SAP and known malignancy or PD were excluded. Whole-body (and where necessary spot/SPECT) Tc-99m HDP BS was performed in all patients. Diagnosis was based on characteristic scintigraphic patterns and radiographic/pathologic correlation. <b>Results</b>: In 67/87 (77%), no significant bone abnormality was identified other than age-related degenerative change (Table). PD was found in 11/87 (13%), including the lowest SAP (126). In three (SAP 136, 138, 293), the major abnormalities were lumbar vertebral body, sacral insufficiency and multiple rib fractures, respectively. In one (SAP 356), abnormal liver uptake on BS led to the diagnosis of colon cancer with extensive lymph node and liver metastases (the likely source of elevated SAP). 5 cases of previously undiagnosed metastatic cancer (4 prostate, 1 lung) (SAP range 215-986, including the 2 highest) were identified. In general, it appeared that for either PD or metastases, the higher the SAP, the greater the bone involvement. <b>Conclusions</b>: Metabolic bone disease and metastases are present over a wide range of SAP levels, reflecting the degree of active metabolism. In general, minor elevations in SAP have a lower incidence of PD or other significant pathology and BS may be better reserved for SAP &gt; 200. Correlation with serum calcium, SAP fractionation and serum PSA (where clinically appropriate) may be alternative approaches to routine BS.
Federal Guidance on HIPAA and Audio-Only Telehealth
Authors: Melissa Suran
Journal: JAMA (2022)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Monkeypox: WHO declares a public health emergency of international concern
Authors: Luke Taylor
Journal: BMJ (2022)

Hypoxia is essential for the development of autoimmune diseases such as rheumatoid arthritis (RA) and is associated with the expression of reactive oxygen species (ROS), because of the enhanced infiltration of immune cells. The aim of this study was to demonstrate the feasibility of measuring hypoxia noninvasively in vivo in arthritic ankles with PET/MRI using the hypoxia tracers <sup>18</sup>F-fluoromisonidazole (<sup>18</sup>F-FMISO) and <sup>18</sup>F-fluoroazomycinarabinoside (<sup>18</sup>F-FAZA). Additionally, we quantified the temporal dynamics of hypoxia and ROS stress using L-012, an ROS-sensitive chemiluminescence optical imaging probe, and analyzed the expression of hypoxia-inducible factors (HIFs). <b>Methods:</b> Mice underwent noninvasive in vivo PET/MRI to measure hypoxia or optical imaging to analyze ROS expression. Additionally, we performed ex vivo pimonidazole-/HIF-1α immunohistochemistry and HIF-1α/2α Western blot/messenger RNA analysis of inflamed and healthy ankles to confirm our in vivo results. <b>Results:</b> Mice diseased from experimental RA exhibited a 3-fold enhancement in hypoxia tracer uptake, even in the early disease stages, and a 45-fold elevation in ROS expression in inflamed ankles compared with the ankles of healthy controls. We further found strong correlations of our noninvasive in vivo hypoxia PET data with pimonidazole and expression of HIF-1α in arthritic ankles. The strongest hypoxia tracer uptake was observed as soon as day 3, whereas the most pronounced ROS stress was evident on day 6 after the onset of experimental RA, indicating that tissue hypoxia can precede ROS stress in RA. <b>Conclusion:</b> Collectively, for the first time to our knowledge, we have demonstrated that the noninvasive measurement of hypoxia in inflammation using <sup>18</sup>F-FAZA and <sup>18</sup>F-FMISO PET imaging represents a promising new tool for uncovering and monitoring rheumatic inflammation in vivo. Further, because hypoxic inflamed tissues are associated with the overexpression of HIFs, specific inhibition of HIFs might represent a new powerful treatment strategy.
Robertsonian Fusion and Centromere Repositioning Contributed to the Formation of Satellite-free Centromeres During the Evolution of Zebras
Authors: Eleonora Cappelletti, Francesca M Piras, Lorenzo Sola, Marco Santagostino, Wasma A Abdelgadir, Elena Raimondi, Francesco Lescai, Solomon G Nergadze, Elena Giulotto
Journal: Molecular Biology and Evolution (2022)

Abstract Centromeres are epigenetically specified by the histone H3 variant CENP-A and typically associated with highly repetitive satellite DNA. We previously discovered natural satellite-free neocentromeres in Equus caballus and Equus asinus. Here, through ChIP-seq with an anti-CENP-A antibody, we found an extraordinarily high number of centromeres lacking satellite DNA in the zebras Equus burchelli (15 of 22) and Equus grevyi (13 of 23), demonstrating that the absence of satellite DNA at the majority of centromeres is compatible with genome stability and species survival and challenging the role of satellite DNA in centromere function. Nine satellite-free centromeres are shared between the two species in agreement with their recent separation. We assembled all centromeric regions and improved the reference genome of E. burchelli. Sequence analysis of the CENP-A binding domains revealed that they are LINE-1 and AT-rich with four of them showing DNA amplification. In the two zebras, satellite-free centromeres emerged from centromere repositioning or following Robertsonian fusion. In five chromosomes, the centromeric function arose near the fusion points, which are located within regions marked by traces of ancestral pericentromeric sequences. Therefore, besides centromere repositioning, Robertsonian fusions are an important source of satellite-free centromeres during evolution. Finally, in one case, a satellite-free centromere was seeded on an inversion breakpoint. At 11 chromosomes, whose primary constrictions seemed to be associated with satellite repeats by cytogenetic analysis, satellite-free neocentromeres were instead located near the ancestral inactivated satellite-based centromeres; therefore, the centromeric function has shifted away from a satellite repeat containing locus to a satellite-free new position.
Use of Daily Patient-Reported Outcome Measurements in Pediatric Cancer Care
Authors: Andreas Meryk, Gabriele Kropshofer, Benjamin Hetzer, David Riedl, Jens Lehmann, Gerhard Rumpold, Alexandra Haid, Verena Schneeberger-Carta, Bernhard Holzner, Roman Crazzolara
Journal: JAMA Network Open (2022)

<h3>Importance</h3> Patient-reported outcome measurements (PROMs) are emerging as an important component of adult cancer care, but little has been done with regard to PROMs for pediatric cancer care. <h3>Objectives</h3> To identify pediatric patients with cancer who are at risk of severe adverse effects of treatment and provide individualized supportive care using PROMs. <h3>Design, Setting, and Participants</h3> This single-center cohort study with PROMs implemented in daily clinical routine was conducted from May 1, 2020, to November 15, 2021, among pediatric patients with a cancer diagnosis or their proxies. Inclusion criteria were treatment with chemotherapy and at least 30 days of active participation. Patients were followed up until completion of therapy or through ongoing therapy until November 15, 2021; data were analyzed from November 15, 2021, through January 31, 2022. <h3>Exposures</h3> Cancer treatment, including chemotherapy, surgery, and radiotherapy. <h3>Main Outcomes and Measures</h3> The primary outcome was occurrence and severity of ubiquitous complications of cancer treatment, such as nausea, appetite loss, pain, sleep disturbance, and deterioration of physical functioning. The secondary outcome was the identification of early and appropriate clinical interventions based on detection of cancer-related symptoms via PROMs. <h3>Results</h3> A total of 4410 daily PROMs from 7082 therapy days for 40 children (35 children aged 5-18 years and 5 proxies for children aged 1-4 years) (median age, 9.1 [IQR, 6.3-12.2] years; 26 [65.0%] male) were analyzed during a median follow-up of 145.5 (IQR, 103.8-244.5) days. All participants were White. The overall median completion rate was 60.1% (IQR, 37.9%-81.0%); this rate was slightly lower during home care vs inpatient stay (57.5% [IQR, 30.7%-85.9%] vs 65.0% [IQR, 49.6%-92.5%], respectively;<i>P</i> = .01), with a decreasing trend over time (65.6% [IQR, 51.6%-85.9%] for the first 90 days vs 42.9% [IQR, 29.3%-82.3%] for beyond 90 days;<i>P</i> &lt; .001). Severe symptoms were reported on 657 days (14.9%); most symptoms were associated with physical functioning, followed by pain, sleep disturbance, and nausea and appetite loss. In total, 321 adverse events (AEs) and cases of health deterioration were documented, and PROMs were completed for 251 (78.2%) of these events. Across all AEs, self-reported pain was the most useful marker, particularly when analyzed on the day before onset, and was associated with an odds ratio of 3.65 (95% CI, 1.54-8.62;<i>P</i> = .005) for the presence of mucositis. <h3>Conclusions and Relevance</h3> The findings of this cohort study suggest that PROMs reflect daily symptoms in pediatric patients with cancer and assist in clinical management and intervention for AEs.
Association of Cerebrospinal Fluid Neurofilament Heavy Protein Levels With Clinical Progression in Patients With Parkinson Disease
Authors: Linbo Wang, Wei Zhang, Fengtao Liu, Chengjie Mao, Chun-Feng Liu, Wei Cheng, Jianfeng Feng
Journal: JAMA Network Open (2022)

<h3>Importance</h3> Neurofilament light in biofluids has been associated with progression of Parkinson disease (PD), but the association between neurofilament heavy (NfH) and progression of PD has not been investigated. <h3>Objective</h3> To evaluate the associations of cerebrospinal fluid (CSF) NfH (cNfH) levels and motor and cognitive progression in PD. <h3>Design, Setting, and Participants</h3> This cohort study used data from the Parkinson Progression Marker Initiative ranging from June 2010 to November 2018. Participants were recruited from 24 participating sites worldwide (United States, Europe, and Australia). Data were analyzed from October 20 to December 18, 2021. <h3>Exposures</h3> Concentrations of NfH in CSF. <h3>Main Outcomes and Measures</h3> The primary outcomes were Movement Disorder Society–sponsored revisions of the Unified Parkinson Disease Rating Scale (MDS-UPDRS) Part III; scores range from 0 to 132, with higher scores indicating worse motor function, and Montreal Cognitive Assessment (MoCA); scores range from 0 to 30, with higher scores indicating better cognitive function. The associations of cNfH levels and longitudinal change in MDS-UPDRS-Part-III and MoCA were examined using linear mixed-effects models with PD duration as the time scale. Partial correlation analysis was conducted to examine the associations of cNfH levels and α-synuclein, amyloid-β 1-42 (Aβ<sub>42)</sub>, phosphorylated tau at threonine 181 position (P-tau), and total tau (T-tau) levels in CSF. <h3>Results</h3> A total of 404 patients with PD (mean [SD] age, 61.7 [9.7] years; 263 were men [65.1%]; within 2 years of diagnosis; Hoehn and Yahr &lt;3) were included. Higher baseline cNfH levels were associated with greater increases in MDS-UPDRS Part-III (β = 0.39; 95% CI, 0.12-0.66;<i>P</i> = .003) and faster decreases in MoCA (β = −0.18; CI, −0.24 to −0.11;<i>P</i> &lt; .001). Levels of cNfH were correlated with CSF levels of α-synuclein (Spearman<i>r</i> = 0.25; 95% CI, 0.15-0.34;<i>P</i> &lt; .001), Aβ<sub>42</sub>(Spearman<i>r</i> = 0.18; 95% CI, 0.08-0.27;<i>P</i> &lt; .001), P-tau (Spearman<i>r</i> = 0.25; 95% CI, 0.15-0.35;<i>P</i> &lt; .001), and T-tau (Spearman<i>r</i> = 0.31; 95% CI, 0.21-0.40;<i>P</i> &lt; .001) at baseline. <h3>Conclusions and Relevance</h3> Higher baseline cNfH levels were associated with faster motor and cognitive progression. This finding suggests that cNfH may be of some value for stratifying patients with PD who have different progression rates.
Access to American College of Surgeons Committee on Trauma–Verified Trauma Centers in the US, 2013-2019
Authors: Jeff Choi, Sarah Karr, Arjun Jain, Taylor C. Harris, Janelle C. Chavez, David A. Spain
Journal: JAMA (2022)

This study uses data from the American Trauma Society’s Trauma Information Exchange Program to evaluate trends in nationwide 60-minute access to American College of Surgeons Committee on Trauma–verified level I-IV trauma centers between 2013 and 2019.
Multidimensional single-cell analysis identifies a role for CD2-CD58 interactions in clinical antitumor T cell responses
Authors: Gabrielle Romain, Paolo Strati, Ali Rezvan, Mohsen Fathi, Irfan N. Bandey, Jay R T. Adolacion, Darren Heeke, Ivan Liadi, Mario L. Marques-Piubelli, Luisa M. Solis, Ankit Mahendra, Francisco Vega, Laurence J.N. Cooper, Harjeet Singh, Mike Mattie, Adrian Bot, Sattva S. Neelapu, Navin Varadarajan
Journal: Journal of Clinical Investigation (2022)

The in vivo persistence of adoptively transferred T cells is predictive of antitumor response. Identifying functional properties of infused T cells that lead to in vivo persistence and tumor eradication has remained elusive. We profiled CD19-specific chimeric antigen receptor (CAR) T cells as the infusion products used to treat large B cell lymphomas using high-throughput single-cell technologies based on time-lapse imaging microscopy in nanowell grids (TIMING), which integrates killing, cytokine secretion, and transcriptional profiling. Our results show that the directional migration of CD19-specific CAR T cells is correlated with multifunctionality. We showed that CD2 on T cells is associated with directional migration and that the interaction between CD2 on T cells and CD58 on lymphoma cells accelerates killing and serial killing. Consistent with this, we observed that elevated CD58 expression on pretreatment tumor samples in patients with relapsed or refractory large B cell lymphomas treated with CD19-specific CAR T cell therapy was associated with complete clinical response and survival. These results highlight the importance of studying dynamic T cell–tumor cell interactions in identifying optimal antitumor responses.
Risk of Adverse Pregnancy Outcomes Among US Individuals With Gestational Diabetes by Race and Ethnicity
Authors: Alison Gemmill, Stephanie A. Leonard
Journal: JAMA (2022)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal